title: MiR-490-3p modulates the proliferation of vascular smooth muscle cells induced by ox-LDL through targeting PAPP-A.
abstract: OBJECTIVE
  Oxidized low-density lipoprotein (ox-LDL) can induce vascular smooth muscle cell (VSMC) proliferation and differentiation, which is the important mechanism of the pro-atherogenic effects of ox-LDL. Although miRNAs are crucial regulators of the ox-LDL effects on VSMC, the detailed mechanisms are not fully elucidated. So, we investigated the miRNAs changes in the proliferation of human coronary artery smooth muscle cells (hCASMCs) induced by ox-LDL and the functional significance of some miRNAs, which were regulated significantly.
  
  
  RESULTS
  Using miRNA microarray, real-time PCR, and luciferase reporter assay, our study showed that miR-490-3p and insulin-like growth factor-1 (IGF1) expression were down-regulated, whereas pregnancy-associated plasma protein A (PAPP-A) and IGF2 expression were up-regulated significantly in hCASMC treated by ox-LDL and/or in human atherosclerotic plaque. Further studies indicated PAPP-A was the target gene of miR-490-3p. The miR-490-3p mimic could inhibit the up-regulation of PAPP-A induced by ox-LDL in hCASMC, which resulted in the suppression of the metalloprotease effect of PAPP-A on IGF-binding protein-4 (IGFBP-4). All these effects led to the inhibition of the proliferation of hCASMC induced by ox-LDL.
  
  
  CONCLUSIONS
  Ox-LDL could inhibit the expression of miR-490-3p and IGF1, whereas increase IGF2 expression. The inhibition of miR0-490-3p up-regulated its target gene PAPP-A and then increased the proteolysis of IGFBP-4. The increased expression of IGF2 and proteolysis of IGFBP-4 might activate pathways independent or dependent on IGF axis by autocrine and paracrine mechanisms and resulted in the VSMC proliferation. Our results could help us to understand the mechanisms of the pro-atherogenic effects of ox-LDL and the effects of PAPP-A on atherosclerosis development.
authors.affiliation: Health Division of Guard Bureau, General Staff Department of Chinese PLA, Beijing, China.
authors.forename: Yufa
authors.initials: Y
authors.lastname: Sun
authors.forename: Deyou
authors.initials: D
authors.lastname: Chen
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Li
authors.forename: Minglong
authors.initials: M
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
mesh_terms: D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000502:physiology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D035683:MicroRNAs / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics*
chemical_list: D002843:Chromatin; D008077:Lipoproteins, LDL; C574862:MIRN490 microRNA, human; D035683:MicroRNAs; C099252:oxidized low density lipoprotein; D011266:Pregnancy-Associated Plasma Protein-A; C579283:PAPPA protein, human
keywords: Atherosclerosis; Ox-LDL; Vascular smooth muscle cells; miRNA